Tumors are supposed to be destroyed by our immune system. So how come we still see tumors?

A big part of the answer is probably that our immune system is very good at destroying proto-tumors, but is not so good at handling those that manage to sneak through and grow to the point of detectability. That splits the first question into two questions: Why do some proto-tumors manage to sneak through, not being eliminated by the immune system? And why is it that detectable tumors are not effectively handled?

The first part, I think, may often be related to cell-intrinsic immune escape mutations. That is, pre-cancerous cells are constantly being attacked by the immune system; in turn (if they survive long enough) they constantly mutate, doing things like damaging the antigen-presentation pathway that makes them recognizable by the immune system. Eventually, they find some configuration that reduces the rate at which they’re killed. Once cancer cell replication is even fractionally greater than destruction,1 a tumor can begin to grow.

So that’s probably the earliest stage of tumor growth. But once tumors reach a certain size, a second factor kicks in. Chronic immune responses are dangerous; after all, the whole point of the immune system is to kill things. The chronic immune response against the growing tumor is now shut down. This has been understood for quite a while — the immune system often becomes “tolerant” of a tumor. More recently, it’s become clear that it’s not merely “tolerance” (which implies that the immune system is simply benignly ignoring the tumor); the presence of a tumor actively forces the immune system to shut itself down, slamming on the brakes rather than just peacefully coasting by.

Brakes are a fundamental part of an active immune response. If you look at diagrams of normal immune responses, they show inverted “U” shaped curves (in here and here, for example), where the response is triggered, rapidly ramps up, hopefully does its thing, and then just as rapidly shuts down to near-background levels once again. There used to be a sort of general feeling that this was a rather passive thing — pathogen stimulates response, response destroys pathogen, no more stimulus, response goes away — but now we understand that the shut-down phase is just as active and dynamic as the upward curve. Just as with the upward phase, there are all kinds of different mechanisms to control the response; one of the most important is the “Regulatory T cell” (TReg). And it’s pretty clear that TRegs are involved in controlling the immune response to tumors (I talked about that here, and links therein).

TRegs have been known for a while (I gave a brief history, including the I-J fiasco, here). The usual description of a TReg includes a number of markers;2 one of the most basic is CD4. CD4 T cells used to be lumped together as “T Helper” cells, but now we have multiple sub-specialties in the CD4 category, and TRegs are one of those specialities.

More recently, TRegs — or at least cells that function the same way as TRegs — have been described in the CD8 population of T cells.3 CD8 T cells are traditionally called “Cytotoxic T lymphocytes” (CTL) (although it’s been increasingly clear that cytotoxicity is just one of many functions a CD8 T cell can offer), but it seems that these variants of CD8s can actively shut down an ongoing immune response, in a specific and targeted way. There seems to be a trend to calling these cells “suppressor cells” rather than “TRegs”. “Suppressor T cells” is an older term that was out of favor for a while, but it’s probably useful to bring it back and distinguish between the natural TRegs and some of the other cells that can do something similar but that have different sources and origins.

At least some of the CD8 suppressor T cells can arise from apparently-conventional CD8 T cells. That is, you can pull CD8 T cells out of a normal mouse’s spleen, and depending on what those cells see and are exposed to, they could progress to being conventional CTL — killing tumor cells, producing interferon and other cytokines, generally being a destructive force — or they could become suppressor CD8 T cells, and actively prevent that destruction from happening.

It turns out that one of the forces that can drive a CD8 T cell into being a suppressor T cell is a tumor. A recent paper from Arthur Hurwitz’s lab4 shows this quite clearly. They had shown previously that transferring specific CD8 T cells into a tumor-bearing mouse resulted in what they called “tolerance”.5 But now they demonstrate that it’s more than that; the transferred CD8s are converted into suppressor T cells that actively shut down immune responses.

Tumor-infiltrating TcR-I cells suppressed the in vitro proliferation of both melanoma Ag-specific CD8+ (37B7) T cells and OVA-specific CD4+ (OT-II) T cells. … Even at a ratio of one TcR-I cell to four responder T cells, we observed 30% suppression of proliferation. 4

This isn’t the only way that tumors escape immune recognition, but (at least for some tumors) it may be an important one. It’s clearly an important consideration for things like tumor vaccines and immune therapy, because it suggests that immunizing with tumor antigens (and thereby generating lots of tumor-specific CD8 T cells) may actually increase the suppressive effect of the tumor.

The conversion of CD8+ effector T cells into suppressor cells may be one mechanism by which tumors restrict the immune response from effectively controlling tumor growth. As subsequent effectors infiltrate the tumor, either following peripheral sensitization or as a result of adoptive transfer therapy, the induced regulatory cells may suppress these new effectors and reduce their ability to confer tumor immunity. This cyclic suppressive process may contribute to the profound loss of antitumor responses following adoptive immunotherapy. 4

(My emphasis.) On the other hand, if this is a common mechanism, then overriding it — which should be possible, using cytokines, specific T cell subsets, and/or targeted receptor ligands — may switch the suppressive population abruptly back into an effector group, turning the brainwashed traitors into resistance fighters.

Destruction would include far more than immune destruction, of course — it would include cells that become differentiated and no longer replicated, cells that outgrow their oxygen supply, cells that undergo apoptosis, and so on[↩]

I’m not sure who made the first identification; this looks as if it’s one of those fields where there were incremental advances, hinting more and more strongly at the presence of these cells, but with no single clearcut starting point. Papers in the early 2000s start to point at regulatory CD8s, and by 2004 a handful of relatively high-profile papers fairly solidly identified them. A 2004 review paper isZimring, J., & Kapp, J. (2004). Identification and Characterization of CD8+ Suppressor T Cells Immunologic Research, 29 (1-3), 303-312 DOI: 10.1385/IR:29:1-3:303[↩]

A question from a layman – is it possible that this immunosuppression mechanism is an adaptation? With notable exceptions like pancreatic cancer, one can live for years with a tumor, while a powerful and prolonged immune response could kill our protohuman ancestors in weeks, not directly, but by starting a vicious cycle of weakness and starvation.

Interesting question. I think the mechanism of immunosuppression is a natural one, for the reason you say — avoiding a chronic immune response. Whether it’s “supposed” to happen this way for tumors, or whether the tumors are happening to take advantage of a natural mechanism, is a much harder question (and probably is too teleological to answer very well). I think most likely it’s the latter, though — the tumors are taking advantage of it, it’s not in the body’s best interest to let the tumors go. Hard or impossible to prove, though.

Ian, I think tumor immunology is also interesting from the dendritic cell perspective. How does a dc receive maturation signals to present tumor antigens optimally to elicit an effector cell population? Or does it not? So that the tolerance induction is a result of the lack of dc maturation signals while presenting tumor antigens.

Yes, one of the major hypotheses for tumor-induced tolerance is effects on DC — not just failure to receive maturation signals, but also active signals (like TGFbeta, and many others) that probably drive the DC into a tolerogenic state. That said, there can also be plenty of potential activators in a tumor environment, mainly through cell death (e.g. through low oxygenation if there’s not enough angiogenesis, and general increased apoptotic cells death etc); so it’s not inevitable that DC will follow the tolerogenic route.

The effect of chemotherapy on immune responsiveness, that I’ve talked about here a couple of times, is proposed to be via increased immunogenicity by increasing cell death — a difference in degree rather than kind, I think.

The effects of chemotherapeutic agents are very interesting indeed. I think that the antiproliferatives are generally immunosuppresive but the idea of hypoxic anti-tumor immune response modulation is intriguing. Hypoxia and inflammation is a very complex mixture in my opinion and just browsing the literature I started to realize how little I know.

While searching, I found it very intriguing that 1. adenosine receptor activation by adenosine produced in hypoxia matures DCs, but at the same time reduces T cell effector responses directly, 2. Contrarily to Teffs, Tregs are activated by adenosine receptor ligation, which in turn produce more adenosine 3. There is a shift towards a Th2 (if you believe in the Th1/Th2 paradigm) response.

Apparently Michail V. Sitkovsky has found his niche in T cells and hypoxia.

I am sure there is more going on than we presently know.

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